Introducing BPA-equivalents: assessing mixture toxicity and substitution of BPA in environmental exposure scenarios

Abstract

Bisphenol A (BPA) is a plastic chemical that has been phased out from many applications because it acts as endocrine disruptor. Numerous structurally similar replacements are already in use, and environmental monitoring data indicates exposure of aquatic ecosystems to mixtures of BPA and its alternatives. As many replacement chemicals elicit similar modes of action and some even have higher relative effect potencies than BPA, it is likely that BPA and its alternatives act together in mixtures. Mixtures of BPA alternatives in concentration ratios as they were detected in the surface water across Europe showed effects that were consistent with the mixture prediction model of concentration addition in in vitro bioassays for cytotoxicity, estrogenicity and mitochondrial toxicity. Even partial agonists contributed to estrogenic effects. In case of the activation of the aryl hydrocarbon receptor, most of the mixture components were not specifically active but rather acted as baseline toxicants and the AhR activation was identified as a cytotoxic burst effect. Simulations showed that the apparently AhR-inactive constituents also contributed to the experimental mixture effect at baseline toxic concentrations. We introduced BPA equivalent concentrations (BPA-EQ) or short BPA-equivalents as a simple communication tool to evaluate the contribution of different alternatives to the mixture effects. BPA-EQ enabled comparison of toxicity data of different bisphenol mixtures, and simulation of different replacement scenarios. For instance, when adding five frequently detected BPA alternatives (BPS, BPF, BPAF, BPE and BPB) to BPA, the total surface water concentrations were ten times higher than of BPA alone, but BPA-EQ for cytotoxicity were 24 times and BPA-EQ for estrogenicity were 12 times higher than BPA alone. Further, BPPH dominated the mixture cytotoxicity and BPZ and BPAF the estrogenicity under this real-world scenario. This and other realistic mixtures comprising three to ten bisphenols indicate that structural analogues of BPA should be evaluated as mixture rather than as individual chemicals. Merely changing substituents on the bisphenol core is likely a “regrettable substitution”.